The primary goal of this SBIR AT Phase I proposal is to establish the proof of concept for a new approach to targeted delivery of antimicrobial agents to sites of infection. The studies proposed in this Phase I SBIR AT application will be specifically focused on demonstrating, for the first time, that novel liposome formulations engineered to release their contents at well-defined temperatures can be used to selectively deliver antimicrobial agents to sites of infection. Our central hypothesis is that the delivery of an antimicrobial agent by thermally sensitive liposomes (TSLs) to an infection site, where elevated temperatures are likely to exist, will result in the immediate release of the antimicrobial compound at the infection site thus resulting in an enhanced therapeutic effect. To establish the viability of this approach, we have chosen Pseudomonas aeruginosa as a model pathogen because of its clinical relevance. Our approach is to formulate a model antibacterial drug, such as amikacin, into TSLs and test them in mouse models of Pseudomonas infection. The antibacterial TSL formulations will be compared against free drug and conventional liposome formulations for enhanced efficacy in both splenic and pulmonary Pseudomonas infection models. PUBLIC HEALTH RELEVANCE: To demonstrate the initial proof of concept for the utility of TSLs, we will use an existing passive loading method to encapsulate amikacin into different TSL formulations. The release temperature of the TSLs will be varied in 1-2 degree increments by changing the lipid composition. Each TSL formulation will be tested in a pulmonary mouse model of Pseudomonas aeruginosa infection. In this model, immunosuppressed mice will be challenged intranasally with 100-200 cfu of Pseudomonas aeruginosa and treated with the candidate TSL formulations at different doses. The mice will be monitored for survival and signs of morbidity. The TSL formulations will also be tested in a splenic Pseudomonas aeruginosa infection model. Immunosuppressed mice will be intraperitoneally challenged with 200 cfu of Pseudomonas aeruginosa. In this model, the bacteria first localize in the spleen and then disseminate into the bloodstream. The mice will be monitored for survival and signs of morbidity. Colony forming units will be determined in both the blood and spleen. [unreadable] [unreadable] [unreadable]